The pharmacokinetics and pharmacodynamics of metoprolol after conventional and controlled-release administration in combination with hydrochlorothiazide in healthy volunteers

Summary We have studied a controlled-release formulation containing metoprolol 100 mg and hydrochlorothiazide 12.5 mg. We compared the pharmacokinetics of both substances and the pharmacodynamics of metoprolol with those of a conventional combination tablet.The controlled-release formulation gave less variable plasma metoprolol concentrations, C_max 138 nmol·l^–1 and C_min 74 nmol·l^–1, whereas for the conventional formulation the mean C_max of metoprolol was 629 nmol·l^–1 and the C_min 20 nmol·l^–1.Despite lower relative systemic availability (68%) for metoprolol from the controlled-release formulation and a smaller AUC, metoprolol from the controlled-release formulation produced a greater total effect, calculated as the area under the curve of the effect on exercise heart rate vs. time (303 vs. 259%·h; P<0.05).Hydrochlorothiazide was rapidly absorbed from both formulations and the plasma concentration profiles were almost superimposable.Controlled-release metoprolol with hydrochlorothiazide combines effective ₁-adrenoceptor blockade for 24 h without affecting the pharmacokinetics of hydrochlorothiazide.     

Drug disposition and modelling before and after gastric bypass: immediate and controlled-release metoprolol formulations

Aims

The aim of the present study was to evaluate the disposition of metoprolol after oral administration of an immediate and controlled-release formulation before and after Roux-en-Y gastric bypass (RYGB) surgery in the same individuals and to validate a physiologically based pharmacokinetic (PBPK) model for predicting oral bioavailability following RYGB.

Methods

A single-dose pharmacokinetic study of metoprolol tartrate 200 mg immediate release and controlled release was performed in 14 volunteers before and 6–8 months after RYGB. The observed data were compared with predicted results from the PBPK modelling and simulation of metoprolol tartrate immediate and controlled-release formulation before and after RYGB.

Results

After administration of metoprolol immediate and controlled release, no statistically significant difference in the observed area under the curve (AUC_0–24 h) was shown, although a tendency towards an increased oral exposure could be observed as the AUC_0–24 h was 32.4% [95% confidence interval (CI) 1.36, 63.5] and 55.9% (95% CI 5.73, 106) higher following RYGB for the immediate and controlled-release formulation, respectively. This could be explained by surgery-related weight loss and a reduced presystemic biotransformation in the proximal gastrointestinal tract. The PBPK values predicted by modelling and simulation were similar to the observed data, confirming its validity.

Conclusions

The disposition of metoprolol from an immediate-release and a controlled-release formulation was not significantly altered after RYGB; there was a tendency to an increase, which was also predicted by PBPK modelling and simulation.     

Steady-State Bioavailability and Day-to-Day Variability of a Multiple-Unit (CR/ZOK) and a Single-Unit (OROS) Delivery System of Metoprolol After Once-Daily Dosing

Steady-state bioavailability and day-to-day variability of plasma levels were evaluated in 18 healthy male subjects in a crossover study of multiple once-daily administration of two novel oral drug delivery systems of metoprolol and an immediate-release tablet (100 mg metoprolol tartrate). Data were collected over two consecutive 24-hr dosing intervals on treatment days 6 and 7. The two extended-release formulations investigated were metoprolol CR/ZOK (95 mg metoprolol succinate), a multiple-unit system consisting of several hundred membrane-coated delivery units, and metoprolol OROS (95 mg metoprolol fumarate), a single-unit osmotic delivery system. The extended drug release and absorption observed after administration of metoprolol CR/ZOK and metoprolol OROS resulted in similar steady-state plasma concentrations after once-daily dosing. Compared to the immediate-release tablet, they produced considerably lower plasma peaks, three- to fourfold higher trough concentrations, 8–9 hr longer mean residence times, and 20% lower relative bioavailability. Moreover, the two once-daily metoprolol products were found bioequivalent in C _max and AUC based on 90% confidence intervals for the mean ratio CR/OROS. Repeated plasma concentration measurements on two consecutive 24-hr periods suggested that all three metoprolol treatments produced reproducible and consistent plasma concentrations from day to day at steady state. Assessment of day-to-day variability, however, resulted in significantly lower variation in AUC for the multiple-unit CR/ZOK formulation compared to the single-unit OROS tablet. These results imply that there may be formulation-related differences in the in vivo behavior of the two products despite their being bioequivalent in extent and rate of absorption.     

Biocomparison of Three Formulations of the S1P1 Receptor Modulator Ponesimod in Healthy Subjects

Background

Ponesimod is a potent selective sphingosine-1-phosphate receptor 1 (S1P₁) modulator, which leads to a reduction in circulating lymphocytes, reflecting their sequestration within lymphoid organs. Modulation of the S1P₁ receptor has been previously described to be an effective treatment of autoimmune diseases (e.g., multiple sclerosis).

Objectives

The aim of this study was to compare the relative bioavailability of two polymorphic forms of ponesimod in capsules (Form A versus Form C; Study 1) and the relative bioavailability of a capsule formulation and a tablet formulation (both polymorphic Form C; Study 2).

Methods

Two open-label, randomized, two-way crossover studies in healthy subjects were performed. In Study 1, 12 male subjects received a single dose of 20 mg of polymorphic Form A or Form C of ponesimod in a capsule. In Study 2, 14 male and female subjects (ratio 1:1) received a single dose of 40 mg of polymorphic Form C of ponesimod in either a capsule or a tablet formulation. Pharmacokinetic and safety variables (clinical laboratory test results, vital signs, and an electrocardiogram) were assessed.

Results

Comparison of the exposure to ponesimod following administration of the formulations in Study 1 showed that the 90 % confidence intervals of the geometric mean ratios for the area under the curve from time zero to infinity (AUC_0–inf), the area under the curve from time zero to the time of the last measurable concentration (AUC_0–t), the terminal half-life (t_½), and the maximum plasma concentration (C_max) were all within the 0.80–1.25 bioequivalence interval. In Study 2, more rapid absorption of ponesimod was observed from the tablet formulation than from the capsule formulation. There were no relevant differences in the safety and tolerability profiles between the different formulations.

Conclusion

The two polymorphic forms of ponesimod and tablet versus capsule formulations were similar in terms of pharmacokinetics, safety, and tolerability.     

Pharmacokinetics of slow-release diltiazem and its effect on atrioventricular conduction in healthy volunteers

Summary The pharmacokinetics and effect of a slow-release and a conventional diltiazem tablet on atrioventricular conduction were compared in a randomized cross-over study after a single dose and at steady state in 12 healthy volunteers.The time to peak concentration was significantly delayed after the slow-release as compared to the conventional tablet, both after a single dose (2.7 vs. 0.9 h) and at steady-state (1.9 vs. 0.9 h). The peak concentration was also significantly reduced. There was no marked loss in bioavailability with the slow-release formulation. The maximal fluctuations in serum diltiazem at steady-state for the slow-release tablet were markedly less than after the conventional tablet (62 vs 87%). The PQ-interval was longer after the conventional tablet as compared to the slow-release tablet (both in doses of 120 mg) after a single dose (187 vs 163 ms) and at steady-state (197 vs 174 ms). The maximal prolongation was seen 1 h after intake of the drug. Heart rate was decreased only by 6–9 beats/min, irrespective of the dose. Slow-release diltiazem appears to have many advantages over a conventional tablet.     

The Site of Absorption in the Small Intestine Determines Diltiazem Bioavailability in the Rabbit

Purpose. Since the ability of the small intestine to biotransform a drug may decrease in distal segments of the intestine, this study aimed to assess whether the site of administration in the small intestine could affect the systemic bioavailability of diltiazem and its two active metabolites, N-desmethyldiltiazem (MA) and desacetyldiltiazem (Ml). Methods. Five mg/kg of diltiazem were administered into the lumen of the proximal (0–30 cm, n = 9) or the distal (150–180 cm) small intestine (n = 7) of anesthetized New Zealand rabbits. Blood samples were drawn from the femoral artery for 6 hours, and diltiazem, MA and M1 were assayed by HPLC. Results. The area under the curve (AUC₀ )of diltiazem administered into the distal small intestine was larger than that estimated when diltiazem was given in the proximal segment (14.20 ± 2.82 vs 8.14 ± 0.88 µg.min/ml, p < 0.05), due to a lower diltiazem oral clearance (440 ± 78 vs 660 ± 55 ml/min/kg, p < 0.05). The AUC_{0 360} of MA was not affected by the site of diltiazem administration, but the AUC_{0 360} of M1 was increased when diltiazem was administered in the distal segment of the small intestine. When administered into the distal segment of the intestine, the molar sum of diltiazem and its active metabolites was 48% greater than when delivered into the 0–30 cm segment of the small intestine; as a consequence, absorption of diltiazem in distal segments of the small intestine may enhance its pharmacological response. Conclusions. The site of absorption into the intestine modulates the bioavailability of diltiazem and its two active metabolites.     

Receptor binding assays in analysing the bioavailability and pharmacodynamic bioequivalence of active drug moieties

The bioavailability and pharmacodynamic bioequivalence of a conventional and an experimental sustained-release formulation of 100 mg metoprolol tartrate were studied in a randomised cross-over study in seven healthy volunteers by assessing over 24 h the plasma kinetics of R,S-metoprolol, its ₁-adrenoceptor binding component, and by determining the extent to which the active drug moiety in plasma occupied rabbit lung ₁-and rat reticulocyte ₂-adrenoceptors.The formulations differed markedly in their kinetic characteristics: the peak plasma concentration (C_max) of R,S-metoprolol after administration of the conventional formulation was 140 ng·ml^–1, (n=7) and it was approximately one-third of that after the sustained-release formulation, 49 ng·ml^–1, (n=6); the AUC_{0–24 h}-values for the formulations were 700 and 310 ng·h·ml^–1, respectively. The C_max for the ₁-adrenoceptor binding component of metoprolol was 180 ng·ml^–1 (n=7) after administration of the conventional, and 74 ng·ml^–1 after administration of the sustained-release formulation. The corresponding AUC_{0–24 h}-values for the receptor binding component were 920 and 470 ng·h·ml^–1 (n=7).Thus, the kinetic differences between R,S-metoprolol and the ₁-receptor binding component were considerable and they were affected by the type of formulation. In general, after administration of the sustained-release formulation, the percentage ₁- and ₂-adrenoceptor occupancy of metoprolol in plasma was 5–15% less than after administration of the conventional formulation. At 0.5–1.5 h after drug intake the average ₁-adrenoceptor occupancy of the conventional formulation varied between 80–90% and that of the sustained release formulation between 20–76%. At these times the differences in receptor occupancy were significant; at 0.5–2 h after drug intake the average ₂-adrenoceptor occupancy of the conventional formulation varied from 20–30%, and that of the sustained-release formulation was 2–17%. At other times the difference in receptor occupancy between the formulations was not significant.The results demonstrate that plasma concentration-kinetics were more discriminating than -adrenoceptor-binding in analysing bioequivalence. It was possible to determine the bioavailability of the active ingredient of metoprolol and to study pharmacodynamic bioequivalence by using receptor binding assays.     

Subjective symptoms and pharmacokinetics/dynamics of metoprolol CR in elderly subjects — a comparison with atenolol

Summary In a double-blind, randomised, cross-over study, the pharmacokinetic/dynamic effects and subjective symptoms of a new controlled-release (CR) formulation of metoprolol (50 and 100 mg) have been compared with atenolol (50 mg) and placebo in 20 elderly healthy subjects.The metoprolol CR formulation displayed an even plasma concentration-time profile over the dosage interval while atenolol produced a peak at 2–4 h. All three active treatments produced significant ₁-blockade at 24 h compared to placebo. Four hours after dose intake, the degree of ₁-blockade was significantly greater with conventional atenolol 50 mg than with either dose of metoprolol CR. Subjective well-being was examined with a self-administered questionnaire (MSE-profile), including three dimensions: Contentment, Vitality and Sleep. No significant differences were detected between placebo and either dose of metoprolol CR. At 2 h, following atenolol, a deterioration in Vitality was observed compared to placebo and metoprolol CR 100 mg. At the end of the dosage interval there was no longer any significant difference between the treatments. Perceived leg fatigue during exercise, evaluated 4 h after dosing, was more pronounced during treatment with atenolol than metoprolol CR 50 mg.The results suggest that the metoprolol CR formulation was not associated with significant effects on subjective well-being, whereas atenolol caused a deterioration at the time of the peak plasma concentration of the drug.     

Bioavailability of morphine after administration of a new bioadhesive buccal tablet

A new bioadhesive buccal morphine tablet was developed for controlled release delivery of drug and improved bioavailability compared with oral controlled release tablet. In order to characterize the pharmacokinetic properties of this bioadhesive buccal formulation, a bioavailability study was performed in 12 healthy volunteers who received: a 30 mg oral controlled release tablet (A); a 20 mg aqueous solution retained in the mouth for 10 min (B); and the 60 mg bioadhesive buccal tablet placed between the lower gum and lip for 6 h (C). The mean amount of morphine absorbed from the solution was very low, only 2 mg of the 20 mg dose. After administration of forms A and C, plasma levels exhibit typical sustained release concentration–time curves. The mean amount of drug recovered from the residual bioadhesive buccal tablet after 6 h indicated that approximately 50% of the dose was released from the bioadhesive buccal tablet. The relative bioavailability of the buccal tablet (corrected for residual unabsorbed dose) compared with the controlled-release tablet was 98% based on the morphine AUC values. Good correlations between the AUC and the C_max of the bioadhesive tablet for the drug and metabolite plotted versus the amount of morphine absorbed were found. © 1998 John Wiley & Sons, Ltd.     

Evaluation of the Pharmacokinetics and Safety of AMG 986 Tablet and Capsule Formulations in Healthy Adult Subjects: A Phase I,Open-Label,Randomized Study

Background and objectiveAMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed for the treatment of heart failure. The current phase I study was conducted to evaluate the pharmacokinetics and safety of a single-dose 200-mg capsule formulation of AMG 986 relative to the tablet formulation in 12 healthy subjects.MethodsIn a two-period, two-way crossover design, eligible subjects were randomized 1:1 to tablet/capsule or capsule/tablet treatment sequences; each treatment sequence lasted for approximately 6 days and comprised six subjects.ResultsFollowing a single oral dose of AMG 986, the geometric mean maximum observed concentration (C_max) values were 9670 ng/mL and 6920 ng/mL and the geometric mean area under the curve from time zero to 120 h (AUC_0–120h) values were 68,000 ng*h/mL and 59,900 ng*h/mL for the tablet and capsule, respectively. The geometric least squares means (90% confidence interval [90% CI]) for the ratios of capsule/tablet were 0.88 (90% CI 0.81–0.96) and 0.72 (90% CI 0.57–0.91) for AUC_0–120h and C_max, respectively. AMG 986 had an acceptable safety profile; all adverse events were grade 1 or 2 in severity.ConclusionThere was a modest 12% decrease in AUC_0–120h and a 28% decrease in C_max with the AMG 986 capsule versus the tablet. These differences are not considered to be clinically relevant, suggesting the capsule formulation can be used in subsequent clinical studies of AMG 986.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40268-022-00388-1.     

Effect of saliva flow rate on saliva phenytoin concentrations: implications for therapeutic monitoring

The effect of atropine-induced reductions in saliva flow rate on saliva phenytoin concentrations were evaluated in a randomised placebo-controlled crossover study in a group of epileptic patients stabilised on the drug.Pretreatment with atropine caused significant reductions in saliva flow rates during the first 4 h, compared to saline. The AUC_{0–4 h} for saliva flow rate was significantly reduced by atropine (245 g vs 327 g) and the saliva phenytoin AUC_{0–4 h} was significantly increased (5.6 g · ml^–1 · h vs 4.5 g · ml^–1 · h) without affecting plasma phenytoin concentrations. The saliva/plasma phenytoin AUC_{0–4 h} ratio was therefore significantly increased by atropine (0.15 vs 0.12). However, there was a poor correlation between saliva/plasma phenytoin concentration ratios and saliva flow rates for the two treatments in the individual patients (correlation coefficient ranged from 0.25 to 0.65).These findings demonstrate that saliva phenytoin concentrations are increased by reductions in saliva flow rate. Caution is therefore required when saliva phenytoin concentrations are used for therapeutic monitoring in the presence of factors which may affect saliva flow rate.     

Nocturnal oxygen saturation and body movement in asthmatics treated with controlled-release preparations of theophylline or terbutaline

Summary Nine adult asthmatics with a history of nocturnal symptoms and with morning dips in peak expiratory flow (PEF) were treated for 10–14 days with 24-h controlled-release preparation of theophylline (Th), or a controlled-release preparation of terbutaline (Te), in a double-blind cross-over experiment.During treatment with 450–900 mg Th in the evening morning, plasma drug levels ranged from 53–95 (mean 73) mol/l. The Te dose was 7.5 mg twice daily. Morning PEF values during Th (mean 338 l·min^–1) and Te (316 l·min^–1) were not significantly different. There were no significant differences between the treatments in average nocturnal oximetric O₂ saturation (91.9% during Th and 91.0% during Te), or the amount of nocturnal body movement, recorded with a static charge sensitive bed (total number of movements 146 during Th and 120 during Te).No difference between the treatments was seen with respect to assessment by the subjects of sleep quality, which was considered fair or good.The findings suggest that in moderately severe asthma, nocturnal oxygenation and sleep quality were similar during the two treatments.     

Comparison of the diuretic effect and absorption of a single dose of furosemide and free and the fixed combinations of furosemide and triamterene in healthy male adults

Summary The absorption and diuretic effect of furosemide 40 mg alone (F), and of the free (F+T) and the fixed (FT) combinations of furosemide 40 mg and triamterene 50 mg have been compared in 12 healthy young men.A slight reduction in the area under the concentration-time curve (AUC) of plasma furosemide was found for the fixed combination (AUC₄₈₀) F 2.58 g · h · ml^–1; F+T 2.46 g · h · ml^–1; FT 1.97 g · h · ml^–1. There was a significant reduction in the AUC₄₈₀ of plasma triameterene (F+T 204.9 g · h · l^–1; FT 130.2 g · h · l^–1). Sodium excretion after F+T and FT was more pronounced than after F (F+T 302 mmol; FT 311 mmol; F 259 mmol). When compared to F alone, there was a reduction in the 24-hour potassium excretion after F+T as well as after FT (F 121 mmol; F+T 104 mmol; FT 107 mmol).It is concluded that the absorption of triamterene was significantly reduced after ingestion of the fixed combination tablet. However, in healthy male adults this had no influence on its natriuretic and potassium-sparing effect as compared to the free combination.     

Effects of a finnish sauna on the pharmacokinetics and haemodynamic actions of propranolol and captopril in healthy volunteers

The effects of a Finnish sauna on propranolol pharmacokinetics and on the pharmacodynamics of propranolol and captopril were studied in healthy, young volunteers (2 males, 6 females) in a double-blind, cross-over trial. The subjects received single oral doses of placebo. propranolol (40 mg) or captopril (12.5 mg) in sauna and control sessions at a one-week interval. The sauna sessions consisted of three repetitive 10-min stays in a sauna (85–100°C, relative humidity 25–35%) separated by two 5-min rest periods in a cool room. Sauna bathing started 35, 50 and 65 min after ingestion of the drugs. Venous blood for plasma propranolol measurement were collected before and 15, 30, 45, 60, 75, 90 min and 2, 3, 4, 5, 7 and 24 h after drug intake. The sauna significantly increased the maximum concentration (C_max 41 vs. 28 ng·ml^–1) of propranolol and the mean plasma propranolol concentration 60 and 90 min, and 2 and 3 h after drug administration. It also significantly increased the AUC_0–5h (119 vs 71 g·h·l_-1) of propranolol from 0 to 5 hours t_max, t_1/2 and AUC_0–24h of propranolol did not differ between the control and sauna sessions. The higher propranolol levels during and after the cessation of sauna bathing did not lead to significant changes in blood pressure or heart rate compared to the control period. Captopril had no major effects on these parameters during the post-sauna phase. The results suggest that a sauna may increase the plasma propranolol concentration, but that did not notably affect the blood pressure or heart rate in healthy, young volunteers during the post-sauna phase.     

Characterization and validation of a pharmacokinetic model for controlled-release oxycodone

1Oxycodone is a strong opioid agonist that is currently available in immediate-release (IR) formulations for the treatment of moderate to severe pain. Recently, controlled-release (CR) oxycodone tablets were developed to provide the benefits of twice-a-day dosing to patients treated with oxycodone. The purpose of this investigation was to develop and validate a pharmacokinetic model for CR oxycodone tablets in comparison with IR oxycodone solution. 2Twenty-four normal male volunteers were enrolled in a single-dose, randomized, analytically blinded, two-way crossover study designed to compare the pharmacokinetics of two 10 mg CR oxycodone tablets with 20 mg IR oxycodone oral solution. Pharmacokinetic models describing the oxycodone plasma concentration vs time profiles of CR tablets and IR solution were derived using NONMEM version IV. The predictive performance of the models was assessed by comparison of predicted oxycodone plasma concentrations with actual oxycodone plasma concentrations observed in a separate group of 21 volunteers who received repeated doses of IR and CR oxycodone for 4 days. 3The unit impulse disposition function of oxycodone was best described by a one-compartment model. Absorption rate of the IR solution was best described by a mono-exponential model with a lag time, whereas absorption rate of the CR tablet was best described using a bi-exponential model. The absorption profile of the CR tablets was characterized by a rapid absorption component ( t_1/2abs=37 min) accounting for 38% of the available dose and a slow absorption phase ( t_1/2abs=6.2 h) accounting for 62% of the available dose. Two 10 mg tablets of oral CR oxycodone hydrochloride were 102.7% bioavailable relative to 20 mg of IR oxycodone hydrochloride oral solution. The population model derived after administration of a single dose accurately predicted both the mean and range of oxycodone concentrations observed during 4 days of repeated dosing. The mean prediction error was 2.7% with a coefficient of variation of 54%. 4The absorption characteristics of CR oxycodone tablets should allow effective plasma concentrations of oxycodone to be reached quickly and for effective concentrations to be maintained for a longer period after dosing compared with the IR oral solution. The CR dosage form has pharmacokinetic characteristics that permit 12 hourly dosing.     

Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts

In a closed metabolic ward the pharmacokinetics of methadone and its primary metabolite (EDDP) were studied in 20 long-term opiate addicts. After administration of the daily oral dose of methadone HCl (mean 60 mg, range 10–225 mg) blood samples were taken and analysed, using a newly developed high-performance liquid chromatography (HPLC) method. The steady-state plasma concentrations of the 20 subjects varied from 65–630 ng·ml^–1 and from 5 to 55 ng·ml^–1, whereas the peak concentrations were 124–1255 ng·ml^–1 and 10 – 301 ng·ml^–1 for methadone and EDDP, respectively. The calculated ratios between the area under the curve (AUC_{(0–24 h)}) for methadone and the AUC_{(0–24 h)} for EDDP varied from 5.9 to 44.6, indicating interindividual differences in metabolic activity. In 19 out of 20 subjects the pharmacokinetics of methadone are best described using a two-compartment model. The mean body clearance was 1.64 ml·min^–1·kg^–1, whereas the mean elimination rate constant () and plasma half-life (t _1/2) were 0.026·h^–1 (range 0.013–0.053·h^–1) and 31.2 h (range 13–53 h), respectively. Differences of gender were also found. A poor correlation was found between the methadone dose and the steady-state level. A much better correlation was found between the normalized steady-state level and the body clearance.     

Clinical pharmacokinetics of high dose mebendazole in patients treated for cystic hydatid disease

Summary The plasma concentrations of mebendazole and its metabolites have been monitored in twelve patients after receiving a 10 mg/kg dose for cystic hydatid disease. The mebendazole plasma concentration-time profiles differed considerably between patients; elimination half-lives ranged from 2.8–9.0 h, time to peak plasma concentration after dosing ranged from 1.5–7.25 h and peak plasma concentrations ranged from 17.5 to 500 ng/ml. The mean peak plasma concentration of mebendazole after an initial dose (69.5 ng/ml) was lower than found in patients during chronic therapy (137.4 ng/ml). The plasma AUC_Ts for the major metabolites of mebendazole (methyl 5-(-hydroxybenzyl)-2-benzimidazole carbamate and 2-amino-5 benzoylbenzimidazole) were about five times the plasma AUC_T found for mebendazole in patients on chronic therapy. It is suggested that the slower clearance of these polar metabolites relative to mebendazole results from enterohepatic recycling. Since mebendazole is also highly plasma protein bound, caution should be observed in administering mebendazole to patients with liver disease. Concentrations of mebendazole found in the tissue and cyst material collected from two patients during surgery ranged from 59.5 to 206.6 ng/g wet weight.     

Boric acid single dose pharmacokinetics after intravenous administration to man

Eighth young adult male volunteers with a basic (alimentary) plasma boric acid concentration of <0.10–0.46 mg/l were given a single dose of boric acid (562–611 mg) by 20 min IV infusion. The plasma concentration curves, followed for 3 days, best fitted a three-compartment open model, although two subjects had to be left out due to inconstant basal plasma concentration values or failure to fit to the three-compartment model. The 120 h urinary excretion was 98.7±9.1% of dose, Cl_tot 54.6±8.0 ml/min/1.73 m², t_1/2 21.0±4.9 h and distribution volumes V₁, V₂, and V₃: 0.251±0.099, 0.456±0.067 and 0.340±0.128 l/kg.     

Interaction between valproate formulation and phenytoin concentrations

Changes in phenytoin concentrations caused by switching valproate formulations with different absorption rates were retrospectively investigated in eleven epileptic patients receiving treatment with both drugs. Total plasma phenytoin concentrations were measured before and after a standard tablet of valproate was replaced by the same dose as a slow-release tablet.The mean plasma phenytoin level rose significantly from 14.4 to 18.7 g·ml^–1. Nine of eleven patients had markedly increased phenytoin levels (by 21 to 72%), and two developed toxic symptoms.The results indicate that changing valproate formulations can cause major alterations in the plasma concentration of co-administered phenytoin.     

On the pharmacokinetics of pengitoxin and its cardioactive derivative 16-acetyl-gitoxin

Summary The pharmacokinetics of pengitoxin has been studied in 28 healthy subjects after intravenous and oral administration. The mean plasma concentration 24 h after 0.5 mg i.v. was 5.2 ng · ml^–1. Following an open two-compartment model a mean elimination half-life of 60.5 h (24.9 to 103.5 h) and a mean volume of distribution (V_darea) of 66.91 (31.8 to 109.61) were calculated. Absorption calculated by comparison of the AUC_0--values amounted to 99%. Within 4 days, 16.7% (11.7 to 21.1%) or 27.8% (18.4 to 33.7%) (0.5 mg i.v. or 1.2 mg p.o.) was excreted in urine. After pengitoxin 0.5 mg i.v. total body clearance and renal clearance were 13.3 ml · min^–1 (7.0 to 18.6 ml · min^–1) and 3.0 ml · min^–1 (1.9 to 3.9 ml · min^–1) respectively. The elimination half-life of pengitoxin is longer than that of digoxin and distinctly shorter than that of digitoxin, whilst its distribution volume and clearance are closer to those of digitoxin than of digoxin.